Etiological Risk Factors

Family history, female gender, neurotic temperament, gene polymorphisms as well as developmental and early life insults, environmental stress, biochemical abnormalities

Pathogenesis Depression

Figure 7.2. Depression pathogenesis. Schematic representation of the ongoing interactions between biological risk factors, exogenous environmental stressors and critical limbic-cortical circuits responsible for maintaining normal responses to ongoing emotionally salient stimuli. Decompensation of this system precipitated by unknown factors leads to a disequilibrium state otherwise know as a major depressive disorder. Adapted & modified from Akiskal & Mckinney (1973).

Figure 7.2. Depression pathogenesis. Schematic representation of the ongoing interactions between biological risk factors, exogenous environmental stressors and critical limbic-cortical circuits responsible for maintaining normal responses to ongoing emotionally salient stimuli. Decompensation of this system precipitated by unknown factors leads to a disequilibrium state otherwise know as a major depressive disorder. Adapted & modified from Akiskal & Mckinney (1973).

and certain brain lesions have all been linked to increased depression vulnerability (Fig. 7.2).

Genetics. Converging evidence from adoption, twin, and family studies point to a significant genetic contribution, although specific markers have yet to be identified (Johansson et al., 2001). Meta-analytic studies of twins identify an overall her-itability of 37 percent with no effect of a shared environment and a 63 percent effect of the unique environment suggesting complex interactions between genes and environment (Sullivan et al., 2000). Linkage studies, however, have yet to define candidate genes, in contrast to the many linked thus far to bipolar disorder. Association studies examining polymorphisms in genes related to monoamine function, on the other hand, have identified several potential targets. One of the most promising is the insertion/deletion polymorphism in the promoter region of the serotonin transporter 5-HTT (Murphy et al., 2001). While the homozygous short allele version of this gene (s/s 5-HTTLPR) has been linked to depression, the association is not disease specific; correlations with anxiety, alcoholism, aggression, and suicidality are also described (Lesch et al., 1996). Furthermore, these findings are extremely variable with many published nonreplications, perhaps reflecting complex interaction of this gene with other functional polymorphisms (i.e., monoamine oxidase-A, catechol-o-methyl-transferase). Notable is a postmortem study demonstrating no correlation of the s/s

5-HTTLPR allele with either a depression diagnosis or the degree of reduced transporter binding in the brainstem and prefrontal cortex of deceased depressed patients (Mann et al., 2000).

Biochemical. Primary dysregulation of specific neurochemicals and neuropeptides is also theorized, supported by abnormalities in platelets, spinal fluid, and postmortem brain samples (Bauer and Frazer, 1994) (see discussion of biochemical biomarkers later in this chapter). Definitive links, however, have not been made to disease pathogenesis, nor are there clear preclinical biochemical markers identifying individuals at risk.

Exogenous Stressors. The influence of environmental factors is equally complex. While no correlations between depression and socioeconomic status, education, cultural background, or specific lifestyle have been demonstrated, stress is a common precipitant (Kendler et al., 2002). Recent studies in both human and animals provide further evidence that early life trauma and abuse, as well as prenatal and perinatal maternal stress may also contribute to an increased vulnerability to develop various types of affective disorders in later life (Heim et al., 2000; Lyons et al., 2000; Sanchez et al., 2001), but causal relationships between stress, disease vulnerability, and precipitation of an acute depressive episode are far from clear. The association of stress-provoking life events with the onset of a major depressive episode does, however, appear to be strongest for the first such episode than for subsequent recurrences. This association continues to hold true over time only for those patients without a positive family history, suggesting a more fundamental brain diathesis in those with genetic risk factors (Kendler et al., 2002). Neuroticism, a personality trait reflecting temperamental hypersensitivity to negative stimuli or the tendency to experience exaggerated negative mood states in situations of emotional instability or dissonance (Costa and McCrae, 1997) appears to be a significant independent risk factor (Roberts and Kendler, 1999). While links between neuroticism and the 5-HTT gene were initially considered quite promising, findings have been difficult to replicate across a number of samples worldwide, possibly due in part to use of different neuroticism scales as well as inconsistent control for gender and family history of depression (Flory et al., 1999; Neumeister et al., 2002). Additional studies are ongoing.

TREATMENT OPTIONS Clinical Management

An untreated major depressive episode generally lasts 6 to 13 months. Treatment, whether with pharmacological or nonpharmacological strategies (APA, 2000), can significantly reduce this period. Empirically, it is well recognized that patients with a poor or incomplete response to one form of treatment often respond well to another. Others will respond to treatment augmentation or combination strategies using drugs with complementary pharmacological actions, combined drug and cognitive behavioral therapy, or in medication-resistant patients electroconvulsive therapy. Such resistance to treatment is reported to occur in 20 to 40 percent of cases. Newer strategies for more severe patients now also include repetitive transcranial magnetic and vagal nerve stimulation, although these are still considered experimental (George et al., 1999; Rush et al., 2000). More rarely, refractory patients are treated neurosurgically with selective lesions in the cingulum bundle, anterior internal capsule, or subcaudate tract (Cosgrove and Rauch, 1995). For patients with mild to moderate as well as more severe depressions, medication and cognitive therapies have been shown to be equal in their efficacy to treat depressive symptoms (DeRubeis et al., 1999). There are, however, no clinical, neurochemical, or imaging biomarkers that can either identify which patients are likely (or unlikely) to respond to a given intervention or predict which patients are vulnerable to relapse during maintenance treatment (Frank and Thase, 1999). While patient subtyping for the purpose of treatment selection has been attempted, there are at present, no clinical algorithms that can reliably determine the necessary and sufficient treatment of individual patients, as is the case for many medical conditions, such as diabetes and ischemic heart disease.

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